Experimental infections of monkeys with lymphotropic SIV strains have indicated that the production of protective immune responses to SIV requires a lengthy and complex maturation of humoral and cellular immune responses. However, little in known about the specificity of these protective immune responses, thus hindering the design of effective vaccine strategies. This NCVDG has recently discovered that inoculation of macaques with attenuated macrophage tropic SIV17E/C1 resulted in a rapid evolution of broadly protective immunity to experimental SIV challenge. These observations suggest that attenuated macrophage tropic SIV vaccines provide a unique model to examine the maturation and specificity of protective immune responses to SIV. This project is designed to characterize the evolution of antibody responses mediating broad protection against SIV and to determine the specificity of the SIV antigenic determinants that elicit these protective immune responses in macaques in monkeys immunized with attenuated SIV vaccines and in monkeys that are long term survivors of infection with pathogenic strains of SIV. The following specific aims are proposed to achieve these objectives: (1) to map conformational and linear antigenic determinants of SIV envelope glycoproteins using rhesus monoclonal and polyclonal antibodies, (2) to determine the specificity of protective antibodies produced in immunized monkeys by analyses of immune serum antibodies fractionated according to their antigenic determinants on SIV envelope proteins, (3) to characterize the evolution of protective antibodies by monitoring critical antibody properties, and (4) to extend these studies with SIV to the SHIV chimeric virus model. It is anticipated that the results of these studies of antibody responses to SIV will provide fundamental new information on SIV envelope protein immunogenicity, elucidate the specificity of protective antibody responses to SIV, and establish critical immune correlates of protection that can be used as performance standards and as prognostic in vitro indicators for evaluating vaccine efficacy in vivo.